Recent data suggest that small changes in acid-base status may play an important role in the development of hypertension and type 2 diabetes. Lower pH may result in higher blood pressure by promoting renal salt- retention and may lead to insulin resistance by inhibiting binding of insulin to its receptors. In healthy participants of the National Health and Nutrition Examination Survey who had blood pressure, fasting glucose, and plasma bicarbonate in ranges considered normal, lower bicarbonate was associated with higher blood pressure and greater insulin resistance, independent of body size and kidney function. Because bicarbonate is the primary buffer in extra-cellular fluid, lower plasma bicarbonate generally reflects lower extra-cellular pH. As part of the compensatory response to acid production, the kidney decreases the amount of citrate lost in the urine - and we previously reported lower 24-hour urinary citrate in Nurses Health Study (NHS) participants with hypertension. High alkali diets (such as the DASH diet) reduce blood pressure, and observational studies report that higher dietary potassium (a marker of alkali intake) is associated with a lower risk of diabetes. Because previous human studies examining the relations between acid-base status, hypertension, and diabetes were cross-sectional, it is unknown whether low-grade metabolic acidosis is a cause or a consequence of these diseases. To determine the independent associations between acid-base status and the subsequent risk of hypertension and type 2 diabetes, we propose the following prospective studies of women in NHS I and II: 1) a nested case-control study of the association between plasma bicarbonate and risk of incident hypertension (N = 1500), 2) a cohort study of the association between 24-hour urinary citrate and risk of incident hypertension (N = 2000), 3) a cohort study of the association between plasma bicarbonate and changes in insulin resistance in women without diabetes (N = 750), and 4) a nested case-control study of the relation between plasma bicarbonate and risk of incident diabetes (N = 1500). This application represents the first large-scale prospective effort to examine the impact of acid-base status on the risk of developing hypertension, insulin resistance, and type 2 diabetes. The unique strengths of this application include 1) updated, detailed exposure information accumulated prospectively over long periods, 2) archived plasma, and 3) large sample sizes providing high statistical power. PUBLIC HEALTH RELEVANCE: We propose to conduct the first prospective studies of the impact of acid-base status on the risk of hypertension and diabetes. We expect our study to provide novel insights into the development of hypertension and diabetes and to suggest new strategies, such as alkali therapy, to prevent these diseases. .